The Ups and Downs of Drug Levels: A Pharmacokinetics Primer

Antiviral medications have a much harder time getting to work than you do. Sure, you have to deal with the bus or subway, or traffic on the streets. But look at what your meds go through! First they get swallowed and dumped into a pool of acid in your stomach. Then they dissolve, leave the stomach and start getting absorbed -- mostly through the lining of the small intestine. Then, the blood from around the intestine carries them to the liver. Now, the liver is an organ that's designed to break down (metabolize) and remove foreign stuff from the blood, so most drugs have a tough time getting past it. With many HIV drugs, only a tiny fraction of the medicine actually gets past the liver and into the bloodstream. So far, this journey is called "first-pass metabolism."

The amount of drug that makes it into your bloodstream, compared to the amount that you put into your mouth, is called its "bioavailability." If a drug has low bioavailability, then much of the drug is destroyed by stomach acid, or is not absorbed in the small intestine, or is removed by first-pass metabolism in the liver. The amount of drug you take in a pill is calculated to correct for this so that the amount you need actually ends up in the blood.

Once drugs are past the liver, the bloodstream carries them throughout the rest of the body in about one minute. But they're still not ready to go to work. Now they have to move from the bloodstream and into the infected cells. But before this happens there are more barriers.

The next problem is called protein binding. Proteins in the blood (albumin and alpha-1 acid glycoprotein) stick to most of the drug in the bloodstream and hold it hostage. This is a normal way to distribute some messengers in the body. For example, adrenalin is produced in the kidneys. Without protein binding, it might get absorbed too soon. But blood proteins capture the adrenalin and carry it all around the body so that some gets to the heart and brain where it is needed.

Protein binding works like a fleet of trucks that load up most of the available drug supply and drive it to locations all over the body. The drug that's not loaded in the trucks is called the "free fraction." This is the only amount that is free to leave the bloodstream and go to work. As the free fraction is used up, the blood proteins gradually unload more of the drug. Some drugs are "highly protein bound" and can't get free. With certain drugs, less than 1% ever gets to leave the bloodstream and go to work in the cells.

Some areas of the body are "high security" zones. For example, the "blood brain barrier," a tightly woven network of blood vessels, protects our brain and spinal cord from toxins but also keeps most antiviral drugs out. Other areas the body protects from outsiders are the testicles and ovaries.

To get inside infected cells where they're needed, drugs have to pass through the cell's membrane. The membrane is protected by chemical "guards" that make sure only the right stuff gets in. For example, the nukes (nucleoside analog reverse transcriptase inhibitors, NRTIs) have an easy time getting past the membrane because they are so similar to natural building materials the cell uses when it divides. Chemical "hands" actually pull them into the cell. But once inside, the nukes still have to go through three more steps of chemical processing (called phosphorylization) before they are ready to work.

The other types of antiviral drugs -- the NNRTIs and PIs -- have a harder time getting inside cells because they don't resemble anything that the cell normally needs. Still, they can push their way inside -- even though a chemical "bouncer"called P-Glycoprotein might push some of the drug back out again.

Do We Have Enough?

With all of these barriers, less than .01% of the medication you swallow might ever make it inside your cells to fight the virus. That's why it's critical to be sure that enough drug gets into the bloodstream to start with. The study of the way drugs are absorbed and move through the body is called pharmacokinetics (far' muh ko kih NEH' tix), or PK, for short.

PK measures the ups and downs of drug levels in your body. For example, when you take a dose of a medication, the drug level in the blood goes up quickly. In a little while, it reaches its peak. This is called Cmax -- the maximum concentration. As the drug is removed (metabolized) from your body by the liver or kidneys, blood levels of the drug drop. Just before the next dose enters your bloodstream, blood levels of the drug are at their lowest. This is called the "trough," or Cmin -- the minimum concentration.

Another PK value measures how long a drug stays in the bloodstream. It is calculated as the amount of time it takes for drug levels to fall by 50%. This is called the "half-life" of the drug.

If you draw a graph of drug levels in the blood, you will see that they rise quickly to the Cmax after a dose is taken, then fall off over time until the next dose.

The same graph can also be used to measure the total exposure to a drug. The "area under the curve," or AUC, is calculated by adding up the area under the curved line that charts the peak and trough levels of a drug.

Drug levels are different in different people. We all know some people who can eat constantly and stay thin, and others who seem to just look at food and gain weight. It's similar with drug levels. Some people "process" drugs quickly and so have lower blood levels -- while others have higher levels with the same dosing. Drug doses are based on PK averages for the people who were studied by the drug company. It's possible that a person should use a lower dose if they don't weigh very much, or if they have a slow metabolism. If you have a large body or a quick metabolism, you might need a higher dose. Your doctor might want to check your blood's drug level if a medicine doesn't seem to work the way it should.

Pharmacokinetics:Therapeutic Window -- Peak and Trough

How Is PK Used?

PK studies help drug companies select a dose for a new drug. The ideal dose should be strong enough to be effective without causing too many side effects. We can start by setting upper and lower limits on drug levels in the blood. This can be shown by the two horizontal lines on our PK graph. The upper line represents the blood level where people start to develop serious side effects. The lower line represents the minimum drug levels that provide good control of the virus. This is usually the drug concentration that cuts down viral replication by 50%. This is called the "inhibitory concentration (50)" or IC50. We want to keep drug concentrations above the IC50, but below the level that will cause serious side effects. The zone between these two lines is called the "therapeutic window" -- the range of drug concentrations where it's doing more good than harm.

Each PK measurement puts some limits on the dosing:

The Cmax is related to short-term side effects like nausea or headache that hit after each dose. The Cmax has to stay low enough to keep these at a safe and tolerable level.

The Cmin relates to control of the virus. If the Cmin drops too low, HIV can multiply and maybe develop resistance to the drug. The higher the Cmin, the better the viral control. Most manufacturers want to see the Cmin stay several times higher than the IC50.

The half-life of the drug determines how often you have to take it. Drugs with a long half-life stay in the blood longer, and might only have to be taken once or twice a day. If a drug has a short half-life, it might have to be taken three or more times a day.

The AUC, which measures total exposure to the drug, is also often related to control of the virus. The higher the AUC, the better the control. It can also be related to the amount of long-term side effects.

Let's say that a drug was approved based on three doses a day. Then the manufacturer wants to make it easier for patients to take, so they try to design a twice-daily dose. To do this, they will rely on PK data.

They start by putting more medication in each dose. Then they try it out on a few people. Is the Cmax too high? Does it cause too much nausea and headache when each dose is taken?

Instead of 8 hours between doses, can the stronger dose be taken every 12 hours? If the drug has a long half-life, maybe there won't be a big difference in the minimum blood levels (Cmin). How does the new Cmin after 12 hours compare to the amount of drug needed to control the virus?

What's the AUC (area under the curve) using the new twice-daily dosing? If it's equal to or higher than the old AUC, then the new dosing will probably be just as powerful against the virus.

With a wide therapeutic window, it's easier to make some of these changes. There's more room to increase the dose without causing bad side effects, and more room (time) to let the blood level drop before it gets too low. With a narrow therapeutic window, there may be just one choice for dosing.

Area Under the Curve (AUC)Measures Total Drug Exposure

The Best Curve Is a Straight Line

The ideal situation is a constant level of drug in the body -- enough to control the virus, but not enough to cause a lot of side effects. Instead of a graph showing peaks and troughs, we'd have a flat line. This will never happen by swallowing pills, because we get a large peak of drug with each dose. The only way to get constant drug levels is with an intravenous (IV) infusion, or with a pump like some diabetics use to take insulin. These methods of taking medication are more expensive and complicated than taking pills. Because they break the skin, there is also a risk of infection.

There is another way, however, to "smooth out" drug levels in the blood. Blood levels drop when the drug is metabolized by the liver and removed from the body. If we slow down this process, less of the drug is removed from the blood. The concentrations stay higher and the drug's half-life is extended.

The protease inhibitor ritonavir (Norvir) has this effect. For example, if the protease inhibitor indinavir (Crixivan) is used by itself, it has to be taken on an empty stomach, three times a day, once every eight hours. The "trough" levels are not much higher than the levels needed to stop the virus. But if indinavir is combined with a small amount of ritonavir, the trough levels of indinavir stay much higher, and you can take it just twice a day, with food. Ritonavir has a similar effect when it's combined with other protease inhibitors. These "ritonavir-boosted" regimens haven't been approved by the FDA yet, but are getting a lot of attention from researchers. Even though ritonavir is a protease inhibitor itself, its ability to slow metabolism of other drugs in the liver is a special use for the drug.

Pharmacokinetics can be very technical, but it's important to study drug levels to help let people control their virus without suffering too many side effects.

Glossary

AUC: Area under the curve, a measure of total exposure to a drug over a 24-hour period.

Bioavailability: A measure of how much drug makes it into the bloodstream, compared to how much we swallow.

Cmax: The maximum concentration of drug in the blood. It occurs shortly after taking a dose.

Cmin: The minimum concentration of drug in the blood. It occurs close to the time before the next dose is taken.

Half-life: A measure of how long a drug stays in the blood. The length of time it takes for the blood concentration to drop to 50% of Cmax.